The acute respiratory distress syndrome, ARDS, occurs in approximately 200,000 Americans each year. A recent worldwide study indicated that ARDS is an underdiagnosed with 10.4% of all patients admitted to the intensive care unit, ICU, fulfilling the ARDS criteria. The pathology includes atelectasis, pulmonary edema, elevated pulmonary dead space and hypoxemia. Despite sophisticated intensive care, many patients with milder hypoxemia (PaO2/FiO2 between 200 and 300 mmHg) deteriorate to ARDS with a PaO2/FiO2<200 mmHg. Despite improved low tidal volume ventilation maintenance the mortality rate still remains at 30-40%.
Although the etiology of ARDS is often multifactorial, common to patients with ARDS is impaired surfactant function and continued inflammation-induced degradation of surfactant's surface tension lowering activity. The volume of aerated lung available for gas exchange and mechanical insufflation is reduced as a result of dense atelectasis predominantly in dependent lung regions. Surfactant's low surface tension helps maintain the patency of the conducting airways and enables the alveoli to open with a reduced work of breathing. Thus aerosol surfactant replacement therapy may provide a life saving treatment regime.
Clinical trials with surfactant aerosols for the treatment of ARDS however, have not shown the anticipated clinical benefit of surfactant administration. Contributing factors to this outcome include:                Insufficient surfactant delivery rate to the lungs        Surfactant not being administered throughout the prolonged surfactant abnormality.        
The delivery of surfactant in a non-invasive manner would allow physicians to provide improved life support and potentially a marked improvement in survival.
Aerosol delivery of surfactant to the lungs may benefit other patients with compromised lung function. This includes the treatment of patients with idiopathic pulmonary fibrosis that has a prevalence rate of 13-20/100,000 population or ˜60,000 patients in the US. In addition, aerosols of surfactant may have therapeutic benefits in patients with neonatal respiratory distress syndrome, NRDS, chronic obstructive pulmonary disease, asthma, cystic fibrosis, and pneumonia. Hospital acquired respiratory infections are a major heath issue and cost an estimated $6 B annually. Treatment of such respiratory infections with anti-infectives by respirable aerosol delivery by systems such as SUPRAER™ could reduce these health costs. Also, it would be an improvement over the prior art if epoprostenol, mucoactive agents and other medications which form solutions or suspensions could be delivered at high delivery rates with viscosities up to at least 39 cSt in a clinical setting. In addition, co-delivery of surfactant with drugs may augment the effectiveness of these drugs.
Biologics are 50% of the drug development pipeline. At least 60 of these are in development for the treatment of lung diseases that are targeted to be delivered intravenously rather than by aerosol. The IV route is most often chosen for the treatment of lung disease with biologics due to the limitations of present aerosol delivery systems and inbuilt perceptions within the pharmaceutical industry. However, intravenous administration not only has considerable patient resistance, but its own attendant complications. Intravenous administration is likely to require a 10 to 100 times higher dose than if it were administered by aerosol inhalation. The ability to deliver these agents directly to the lungs in form of respirable aerosol markedly reduces the total dose of the agent, the cost of therapy, as well as systemic toxicities.
Non-small-cell lung cancer is treated with cocktails of drugs delivered intravenously. Twenty four biologics for lung cancer are in clinical trials and 12 in the market.
With IV administration:                2-15% treats the lungs        >85% exposes other organs        Dose 10-100 times that of aerosol inhalation        
Aerosol delivery results in;                Lower doses administered        Less systemic side-effects        
Lower treatment costs and potentially better outcomes.
An estimate of effective dose of surfactant delivered by aerosol in patients with ARDS provides guidance as to the dose rate and total dose of surfactant aerosol that is necessary to be delivered by an aerosolizing device. Delivery of 2-7.5 mg/kg of surfactant aerosol has been shown to be effective in neonatal lambs. Windtree Therapeutics delivered 100 mg/hour or 0.03 mg/s of aerosolized surfactant to neonates but it is considered likely that only a small percentage of this was delivered to the lungs. In ARDS there is inactivation of the surfactant by proteins and phospholipases and thus a higher dose delivered to the lungs may be desirable. The mass of surfactant in healthy lungs has been estimated to be 5-10 mg/kg. Thus total surfactant replacement in a 70 kg patient will require 350-700 mg to be deposited in the lungs. Thus, clinically relevant therapeutic doses between 300 mg and 1 g of surfactant aerosol deposited in the lungs are likely required for efficacy. Due to continued inflammation-induced degradation of surfactant in this aerosol surfactant replacement therapy may be required to be repeated on multiple occasions.
Delivery of a sufficient mass of aerosolized surfactant of aerosols between 1.5 μm and 4 μm mass median aerodynamic diameter to penetrate to and deposit in the peripheral lung to treat surfactant abnormalities and its continued depletion has been a recalcitrant problem for many years. There are several issues to be overcome related to aerosol particle size, dose rate and uniformity of dose rate as well as the concentration of the aerosol and total dose output.
The output of jet-type nebulizers that produce 3 μm particles and rely on the Venturi effect for the fluid feed to the orifice produce is low (≤0.3 ml/min) and decreases with increasing fluid viscosity (surfactant concentration). The concentration of surfactant in the device increases with atomization time. In addition, foaming can further reduce their output.
The viscosity of surfactant suspensions increases rapidly with surfactant concentration. High concentrations of surfactant have viscosities considerably higher than some mesh-type nebulizers can aerosolize (4 cP) It took 3 hours to deliver 72 mg of a surfactant aerosol at 1.9 μm MMAD.
An aerosol delivery system has been used by Windtree Therapeutics to deliver aerosolized surfactant to neonates. In this system, described in U.S. Pat. No. 6,234,167 B1, a surfactant suspension is heated and vaporized as it passes through a capillary tube. The condensate forms the aerosol to be delivered. In clinical trials of this system in neonates it produces 100 mg/hour (0.03 mg/s) surfactant aerosol at a flow rate of 3 l/min, i.e. 0.6 mg/l.
A method of generating high concentrations of fine particle aerosols has been described in the U.S. Pat. No. 8,596,268 B2 which is incorporated by reference in its entirety. Briefly, a syringe pump is used to feed an aqueous solution/suspension to an aerosolizing nozzle. This nozzle aerosolizes 100% of the fluid to form a liquid aerosol with a narrow size distribution (σg<2). This aerosol plume is arrested with a co-axial counter-flow of gas. The fluid is evaporated from the particles using a combination of warm compressed gas, and dilution gas together with infrared radiation whose wavelength is optimized for the absorption band of water. The resultant dry particle aerosol is concentrated using a multiple slit virtual impactor with radially aligned acceleration and deceleration nozzles. The particles gain momentum as they pass through the acceleration nozzles. They cross a small gap and lose momentum as they pass through the deceleration nozzles to form a low velocity aerosol. Most of the gas exits the aerosol stream through the gap between these nozzles. As a consequence, the low velocity aerosol is comprised of a considerably higher concentration of particles in a much smaller volume of gas. This aerosol flows through port at 3 cm of water pressure where it can be inhaled on demand. However, for deep lung deposition in patients with compromised lung function aerosols with even smaller diameters at higher delivery rates and high total payloads are desirable to treat patients with ARDS and other lung syndromes and diseases. It is therefore an object of the invention to produce smaller particles at higher concentrations at higher efficiencies together with high clinically relevant payloads.
Heliox, a mixture of helium and oxygen, typically 80% helium and 20% oxygen or 70% helium and 30% oxygen, has been used to improve the effect of bronchodilators and gas exchange in patients with compromised lung function and enhance aerosol deposition in the peripheral lung and thus offers an attractive option for the delivery of therapeutic aerosols. In studies using 70/30 heliox at constant atomizer gas flow to generate aerosols showed that the heliox generated larger particles than air at all tested flow rates However, using the invention described herein accomplishes a marked decrease in aerosol particle size with heliox compared to air at the same compressed gas pressure.
A number of virtual impactors have been described to concentrate aerosols. For example, some linear slit concentrators use a converging channel with a rectangular “v” shaped design as noted above. The mass loading of an aerosol being concentrated can decrease the efficiency of the concentrator and lead to nozzle clogging above concentrations of 1 mg/l. To deliver very high payloads, the aerosol is likely already at a high concentration prior to it being further concentrated. Aerosol deposition on the surfaces of the concentrator must not impair its function during the generation and delivery of this designated payload. Aerosol concentrators that meet the performance of the incident invention have not been described.
As virtual impactors are dependent on the inertia of the aerosol particles, high efficiencies for concentrating particles less that 4 μm MMAD have be difficult to attain, especially with low pressure differentials. For simplicity and clinical utility, it is desirable when concentrating an aerosol using virtual impaction, that this is accomplished at a small positive pressure together such that it can be delivered to the patient at a slight positive pressure without the use of pumps to remove the exhausted gas. This requirement essentially eliminates the use of virtual impactors with high flow resistance such as those using round orifices. Slit orifices have a much lower resistance to gas flow and are thus used in the incident invention. Aerodynamically designed acceleration and deceleration nozzles reduce resistance to flow and improve the concentrator efficiency. U.S. Pat. No. 8,375,987 meets these requirements and is hereby included in its entirety. However, the incident invention provides for the generation and processing of smaller particles with less wall losses and higher aerosol concentrations that can be delivered at higher payloads.
As noted above, the technology for the delivery of surfactant aerosols for inhalation neither incorporates the technologies of the incident invention nor provides the aerosol concentrations and delivery criteria present in the incident invention.